Aspergillus

MICROBIOLOGY

Contamination of air in medical units can occur with construction/renovation unless preventative control measures are implemented.

In the environment (and on culture plates) Aspergillus grows in the vegetative state that is composed of long filamentous structures (hyphae) attached to the substrate upon which the fungus is feeding AND as aerial hyphae, which including a distinctive appearance that resembles an aspergillum (an instrument used for sprinkling holy water in Roman Catholic and Anglican traditions) with associated spores (called conidia) [Fig] .

Conidia: spherical structure, 2-5 µm wide, very easily airborne and hardy that may settle in the sinuses and lower respiratory tract.

If the conidia are not cleared out of the sinuses and airway, they may germinate to form hyphae, invade blood vessels and parenchymal tissue, and use the human host as a substrate for vegetative growth.

CLINICAL

Disease types: respiratory tract most common site of infection (lung, sinuses, large airways).

Other sites include skin, eye, ears, CNS, bone/joint, mediastinum, heart, liver and kidneys. Infection in those cases is due to direct inoculation during a medical procedure or trauma or from disseminated disease.

Invasive infection:

The intensity and rapidity of progression often depends on the extent of immunosuppression and possibly, genetic factors. Lungs are most commonly involved sites where disease spectrum includes chronic cavitary, chronic fibrosing, subacute invasive (also called chronic necrotizing) and acute invasive variants.

Allergic bronchopulmonary aspergillosis (ABPA): often seen in patients with asthma or cystic fibrosis.

Allergic sinusitis

Aspergilloma: presence of Aspergillus fungus ball in preexisting pulmonary cavity. Clinical manifestations range from single and stable aspergilloma to presence of fungus ball(s) in the context of chronic cavitary aspergillosis.

Diagnosis: usually by combination of host status, imaging and mycological findings. Early diagnosis and treatment is critical in management.

In the appropriate patient (e.g., neutropenic), the presence of nodules ≥ 1 cm in diameter are suggestive of a filamantous fungal infection, usually aspergillosis.

Halo/crescent sign predominantly applies to neutropenic populations and is suggestive of, but not definitive evidence for aspergillosis.

Developing invasive pulmonary aspergillosis while neutropenic, radiographic findings may appear to progress with recovery of neutrophils. Nodules may cavitate and apparent aspergillomas may develop at sites of pulmonary infiltrates.

BAL galactomannan greatly facilitates early diagnosis in high-risk patients, but must be interpreted with caution due to cross reactions to other fungi and inability to differentiate airway colonization vs. invasive disease based soley on this test.

Cutaneous: determine if due to dissemination from primary focus, should be treated with systemic voriconazole (+/- echinocandin) or alternatively, AmB product, isavuconazole, posaconazole or echinocandin.

If due to primary cutaneous process (e.g. following trauma), may require surgical debridement in addition to antifungal therapy.

Selected Drug Comments

Drug

Recommendation

Voriconazole

(Vfend) Preferred drug for aspergillus infections based on improved mortality compared to AmB in the treatment of invasive aspergillosis. Advantages are PO and IV formulations, good tolerance, Good CNS penetration and good in vitro and in vivo activity. Drug interactions may be troublesome especially in transplant populations. Parenteral form might be problematic in renal failure, but recent data more reassuring regarding safety. Therapeutic drug monitoring (serum trough levels) seems to be important for improving efficacy and reducing toxicity.

Well tolerated parenteral drugs; however, exact role as monotherapy in the treatment of serious aspergillus infection is unclear. Use in combination therapy with voriconazole and may result in improved outcomes.

Caspofungin acetate

Well tolerated parenteral drugs; however, exact role as monotherapy in the treatment of serious aspergillus infection is unclear. Use in combination therapy with voriconazole and may result in improved outcomes.

Well tolerated parenteral drugs; however, exact role as monotherapy in the treatment of serious aspergillus infection is unclear. Use in combination therapy with voriconazole and may result in improved outcomes.

(Ambisome) The lipid formulations of amphotericin B were initially compared w/ conventional AmB in pts with aspergillosis. Results of these studies show an advantage for the lipid amphotericin formulations, but only for reduction in adverse reactions. The clinical outcome compared to conventional has generally been the same, but the side effects are substantially reduced with the lipid preparations. The cost differential is large.

The lipid formulations of amphotericin B were initially compared w/ conventional AmB in pts with aspergillosis. Results of these studies show an advantage for the lipid amphotericin formulations, but only for reduction in adverse reactions. The clinical outcome compared to conventional has generally been the same, but the side effects are substantially reduced with the lipid preparations. The cost differential is large.

Amphotericin B deoxycholate

Used for severe disease (invasive aspergillosis). In one of the most common forms, invasive pulmonary in compromised hosts especially with neutropenia +/- reduced cell mediated immunity, initial reports showed almost 100% mortality. Now there is substantial survival due to rapid dx and if very high doses of amphotericin are used, though voriconazole has now supplanted as first-line therapy.

(Noxafil) Alternative azole available in oral solution, dealyed release tablet and IV formulation that is FDA approved for the prevention of Aspergillus and Candida as invasive fungal infections in patients at risk. An alternative to voriconazole for patients with aspergillosis. Time to steady state levels can be nearly a week for the tablet and even longer for the solution formulations.

Cannot be used as a single agent for aspergillus infections. It is sometimes combined with amphotericin B as a desperation maneuver, especially with CNS infections due to the more favorable penetration of 5FC across the blood-brain barrier.

Basis for recommendation

Randomized study of voriconazole +/-anidulafungin in patients with hematological malignancy or hematopoietic stem cell transplant and invasive aspergillosis. Key findings: a. Overall mortality was same in monotherapy and combination group, b. Survival was better in combination therapy than monotherapy for those whose aspergillosis diagnosis was established by radiographic findings and galactomannan positivity.

Comment: This study is based on 181 measurements of voriconazole levels and showed, despite standard dosing, 31% showed levels considered potentially toxic and 25% showed levels considered subtherapeutic.

Comment: Review of PCR to detect aspergillus in blood samples to facilitate diagnosis of invasive aspergillus. Summary of 17 studies with 1,191 at risk patients showed sensitivity of 0.91 and specificity of 0.92. However, authors concluded that the technique still needs to be standardized.Rating: Important

Comment: Meta-analysis of 15 studies to evaluate the use of (1-3)-B-D-Glucan (BG). Sensitivity and specificity were 0.76 and 0.85, respectively. Subset analysis showed better specificity with positive results with two positive tests in patients with hematologic malignancies and when combined with galactomannan.Rating: Important

Comment: Author is major authority on aspergillus. For galactomannan the sensitivity for detecting invasive aspergillosis is best in high risk in patients. It is reported as high as 92%, but more recent studies show 40-50% sensitivity. Specificity in high risk patients is >90%. The 1, 3 beta-D-glucan test is somewhat early in development and nonspecific since other fungi including Candida have this cell wall constituent.Rating: Important

Comment: Comparison of serum PCR and galactomannan in patients with hematological malignancies and chemotherapy. Results: sensitivity GM 88%, PCR 75%; specificity GM 93%, PCR 92%. BAL was sometimes positive by either method when serum was negative. Two or more positive tests improved specificity of both.Rating: Important

Comment: Allergic fungal sinusitis is a non-invasive form of sinusitis that accounts for 6-9% of surgeries for rhinosinusitis. Major pathogens: aspergillus, Bipolaris and Curvularia species. Rating: Important

Comment: Serum galactomannan is a non-invasive, widely available, reproducible test that is FDA cleared for use as a surrogate marker of invasive aspergillosis. This paper is a correlation between serum aspergillus galactomannan levels and outcome. Rating: Important

De Pauw B et al: Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 46:1813, 2008 [PMID:18462102]

Comment: This is the NIH Mycosis Study Group criteria for the diagnosis of invasive aspergillosis which combines host factors, radiologic findings and mycotic criteria. Rating: Important

Comment: Review from Seattle on the utility of the assay for Aspergillus galactomannan. The controversial concern regards the performance of the test. Now that the test is widely available it is assumed that there will be large trials with definitive answers.

Comment: The cumulative incidence from 19 sites in the US with 4621 HSCT at 12 months was 0.5% after autologous transplant, 2.3% with an HLA matched donor and 3.9% with an unrelated donor. For 410 organ transplant recipients it was at 12 months it was: lung-2.4%, heart 0.8%, liver 0.3%, kidney -0.1%. The 3 month mortality ranged from 20% for lung transplants to 67% for heart and kidney. The dominant species were A fumigatus -56%, A flavus -19%, A. terreus-16% and A. niger-8%.

Comment: Allergic form is associated with Type I, II and IV allergic responses to Aspergillus antigens. Clinical presentation is bronchiectasis, and airway destruction. May be asymptomatic. Treatment is corticosteroids; surgery may be definitive in some cases but many have inadequate lung reserve.

Comment: This report showed the potential efficacy of itraconazole as the best and then currently only available azole for aspergillosis. The "cure/improve" rate in these studies was 63%. Diagnostic criteria for study purposes were defined as: histopathology showing septate hyphae measuring 2-4u in width with acute angle branching + culture yielding aspergillus. This fungus is difficult to distinguish histologically from Fusarium and P. boydii.

Comment: The initial trials for drug registration for the 3 commercially available lipid formulations of amphotericin B were done with aspergillosis. The initial FDA approval was consequently for aspergillosis. These trials showed the lipid formulations were not clinically superior to conventional amphotericin B, but they were less toxic.

Comment: The authors present a case and a graphic picture of aspergillosis at a Hickman catheter insertion site. The lesion showed concentric plaque lesions of diverse colors. Therapy required removal of the catheter and antifungals.

Comment: This is the original description of the "halo sign" (nodular lung lesion with surrounding area of low attenuation) as an early sign, and the later "crescent sign" (air crescent at periphery of lung nodule).

Comment: The operative mortality for surgical resection of aspergillus fungus balls was 7%, and post-op complications included B-P fistulae and hemorrhage. The recommendation is to reserve surgery for cases that show severe hemoptysis and show adequate pulmonary reserve.